According to the Merck Manual, 12th Edition (D. N. Holvey, M.D., Editor--1972), gout is a recurrent acute arthritis of peripheral joints affecting chiefly mature males and resulting from the deposition in and about the joints and tendons of crystals of monosodium urate. Sodium urate deposits in these places because the patient is hyperuracemic; i.e., his serum levels of urate are elevated to a point at which the solubility of sodium urate is exceeded. Acute attacks of gouty arthritis are treated by the use of an anti-inflammatory drug. The use of colchicine prophylactically will prevent further acute attacks of gout. Uricosuric drugs such as probenecid and sulfinpyrazone can be employed to maintain the serum urate concentration within the normal range.
An alternate method of treatment of gout involves the use of drugs which block the production of uric acid in the mammalian body by blocking the enzyme xanthine oxidase which enzyme converts both hypoxanthine to xanthine and xanthine to uric acid. One such drug is allopurinol (4-hydroxypyrazolo[3,4-d]pyrimidine), an isomer of hypoxanthine. Xanthine oxidase converts this drug to alloxanthine. The competitive conversions of hypoxanthine to xanthine and xanthine to uric acid are thus inhibited and uric acid does not accumulate in the blood. Allopurinol treatment has the further advantage of dissolving uric acid from tophi. Because of its different mechanism of action, allopurinol does not interfere with the effectiveness of the uricosuric drugs, probenecid and sulfinpyrazone, nor with the use of colchicine. Not all patients are able to tolerate allopurinol, however, and it is an object of this invention to provide a drug having the desirable properties of allopurinol without some of its undesirable side effects.
3-Aryl-5-isothiazolecarboxylic acids are known. For example, Naito et al., Chem. Pharm. Bull., 16, 148 (1960) reacted 3-phenyl-4-bromo-5-isothiazolyl lithium with dimethylformamide to yield 4-bromo-5-formyl-3-phenylisothiazole which compound could be oxidized to yield 3-phenyl-4-bromo-5-isothiazolecarboxylic acid. 3-Phenyl-5-isothiazolecarboxylic acid also has been prepared on several occasions. Beringer et al., Helv. Chim. Acta., 49, 2466 (1966) prepared 3-phenylisothiazole from 3-phenyl-5-aminoisothiazole via a diazonium salt. 3-Phenylisothiazole, on treatment with butyllithium followed by treatment with carbon dioxide, yielded 3-phenyl-5-isothiazolecarboxylic acid. Erlenmeyer et al., Ibid, 51, 39 (1968) measured the stability constants of certain acids including 3-phenyl-5-isothiazolecarboxylic acid. Frann and Black, Tetrahedron Letters, 1381 (1970) found that a reaction of 5-phenyl-1,3,4-oxathiazol-2-one and two molar equivalents of ethyl propiolate yielded a mixture of the isomeric esters, ethyl 3-phenyl-4-isothiazolecarboxylate and ethyl 3-phenyl-5-isothiazolecarboxylate. Howe et al., J. Org. Chem., 43, 3732-3736 (1978) prepared mixtures of the same two isothiazole esters carrying at the 3-position a m-trifluoromethylphenyl group, a phenyl group, a 4-chlorophenyl group, a 4-cyanophenyl group and a 3,5-dimethoxyphenyl group. Ethyl 3-phenyl-5-isothiazolecarboxylate and the corresponding methyl ester are disclosed in J. Org. Chem., 44, 510 (1979). Methyl 3-phenyl-4-amino-5-isothiazolecarboxylate and the corresponding ethyl ester are disclosed in a paper by Gewald and Bellmann, Ann., 1534 (1979). In none of the above publications is there any reference to a pharmacological action for any of the isothiazolecarboxylic acids or esters described therein and in particular there is no disclosure of any xanthine oxidase activity possessed by such acids or esters.